tbuckley/cabot-search huggingface dataset:
Abstract 1556: Long non-coding RNA <i>WNT5A-AS1</i> shows sex-dimorphic differences in survival for males with glioblastoma
Authors: Aunay Miller, Junwen Wang, Joseph Loftus, Nhan L. Tran
Journal: Cancer Research (2022)

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median survival time of 12-15 months and 5-year survival rate of 5%. Despite the application of advanced genetics and biological breakthroughs in GBM, the outcome for GBM remains dismal. Previous genome-wide association studies (GWAS) for GBM shows that the incidence rate for GBM in males is 1.6 times higher in men than women, with men displaying overall worse outcomes. In-vivo studies in gender-matched isogenic murine astrocytic cell lines show that the rate of astrocytic transformation is higher in males than in females, corroborating the GWAS findings in human GBM. Thus, understanding how sex effects GBM biology may provide insight into the mechanism of gliomagenesis and response to therapy. To explore the molecular mechanisms by which transformation of GBM increases in males, we used DESeq2 to assess differentially expressed genes between male and female patients. We found that a long non-coding RNA WNT5A-AS1 is overexpressed in males [log2(fold change) of 1.40; FDR = 0.036], regardless of cofounding factors such as IDH1 status, age, and race. Next, we examined if expression of WNT5A-AS1 is correlated with survival within male patients versus female patients in the TCGA-GBM dataset. In males, WNT5A-AS1’s expression is significantly correlated with patient overall survival (P = 0.042, N=109), but not in female (P = 0.585, N=60). Male patients with high expression of WNT5A-AS1 display poor survival outcomes compared to males with low expression. WNT5A-AS1 is located in the upstream, promoter region of WNT5A. Q-PCR quantification of WNT5A expression increases in male GBM specimens as compared to GBM specimens from females. The role that WNT5A-AS1 plays in regulating WNT5A expression is unclear to date. Interestingly, WNT5A expression shows a positive correlation with patient survival in males, with high expression displaying better survival outcomes (p=0.0272). We have data obtained from a subset of patient samples showing an inverse relationship between WNT5A and WNT5A-AS1 expression. This suggests that there may be an inverse correlation between WNT5A-AS1 and WNT5A expression, which elucidates that WNT5A-AS1 may be regulating WNT5A expression. Current ongoing studies will evaluate the role of WNT5A-AS1/WNT5A in sex-differences of GBM progression. Citation Format: Aunay Miller, Junwen Wang, Joseph Loftus, Nhan L. Tran. Long non-coding RNA WNT5A-AS1 shows sex-dimorphic differences in survival for males with glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1556.
Abstract 6094: SRC inhibitor saracatinib enhances efficacy of PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer
Authors: Fei-Teng Lu, Fan Luo, Miao-Zhen Qiu, Jia-Xin Cao, Qiu-Yun Luo, Da-Jun Yang, Hong-Yun Zhao
Journal: Cancer Research (2022)

Abstract Background: Although immune checkpoint inhibitors (ICI) included PD-1/PD-L1 have demonstrated durable therapeutic responses in some cases, a significant portion of patients with cancer remain nonresponsive (e.g. only ~20% with anti-PD-1 in lung cancer). Substantial limitations in the rate of response underscore the need for suitable combination therapies. SRC family kinases is overexpressed or activated in multiple human malignancies, as a candidate target in regulating antitumor immunity. Saracatinib, an orally bioavailable multi-kinase inhibitor, has demonstrated clinical efficacy in CML. Here, we proved saracatinib as SRC inhibitor that were capable of increasing the antitumor immunity in non-small lung cancer. Method: Cytotoxicity assays were used to determined antitumor activities of saracatinib in non-small lung cancer cell lines. The expression of PD-L1 expression in saracatinib 1 treated cell lines was investigated by western blots, quantitative PCR and flow cytometry. The effect of saracatinib in antitumor immunity alone or in combination with immunotherapy was also determined in vitro and in vivo. RNAi, overexpression, and gene expression analyses were used to define underlying mechanisms. Result: We found that SRC inhibitor saracatinib robustly decreased expression of PD-L1 in non-small lung cancer cells and animal models. The observed inhibitory effect was time- and concentration-dependent. Furthermore, our results showed that saracatinib and anti-PD-L1 combined to improve T-cell-mediated killing of tumor cells in vitro and in vivo, which were associated with activation of CD8+ T cytotoxic cell included expression of IFN-γ and granzyme-B. Prolonged survival was also observed in mice treated with saracatinib in combination with PD-L1 blockade. Conclusion: Our in vivo and in vitro data demonstrated that SRC inhibitor saracatinib enhance T-cell-mediated anti-tumor immune responses in non-small lung cancer. We also provide evidence that support the combination of saracatinib and anti-PD-1/PD-L1 as a potential combination therapeutic approach to increase the efficacy of immunotherapy in non-small lung cancer. Citation Format: Fei-Teng Lu, Fan Luo, Miao-Zhen Qiu, Jia-Xin Cao, Qiu-Yun Luo, Da-Jun Yang, Hong-Yun Zhao. SRC inhibitor saracatinib enhances efficacy of PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6094.
The recent outbreak of acute severe hepatitis in children of unknown origin – what is known so far
Authors: Eberhard Lurz, Dominic Lenz, Philip Bufler, Alexander Fichtner, Stephan Henning, Martin Jankofsky, Simone Kathemann, Michael Melter, Jun Oh, Eva Doreen Pfister, Ekkehard Sturm, Birgit Knoppke, Elke Lainka
Journal: Journal of Hepatology (2022)
Upper and Lower Airway Dysanapsis and Airflow Obstruction among Older Adults
Authors: Benjamin M. Smith, Andrew Wiemken, Eric A. Hoffman, Brendan T. Keenan, Norrina B. Allen, Alain G. Bertoni, David R. Jacobs, Erin D. Michos, Karol E. Watson, Susan Redline, Richard J. Schwab, R. Graham Barr, Susan R. Heckbert
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Upper and Lower Airway Dysanapsis and Airflow Obstruction among Older Adults." American Journal of Respiratory and Critical Care Medicine, 206(7), pp. 913–917
Abstract 4076: Single cell RNA analysis reveals heterogeneous sub populations in aggressive variants of prostate cancer
Authors: Rosalia Quezada Urban, Shivakumar Keerthikumar, Ashlee K. Clark, Laura H. Porter, Mitchell G. Lawrence, Renea A. Taylor, Gail P. Risbridger, Roxanne Toivanen, David L. Goode
Journal: Cancer Research (2022)

Abstract Neuroendocrine prostate cancer (NEPC) represent an aggressive malignancy that results in poor patients outcomes. At a histological level, NEPC exhibits heterogeneous pathologies; nevertheless, the molecular features, drivers and therapeutic implications of this heterogeneity are poorly understood. Single cell technology enables the resolution needed to unveil the complex heterogeneity of NEPC that bulk RNA analysis could not previously detect. Therefore, we aim to characterize the molecular heterogeneity of NEPC at a single cell level to detect common phenotypes across patients and identify new therapeutic targets. We performed single cell RNA sequencing on a novel cohort of nine patient derived xenograft (PDX) models that recapitulate the pathological and clinical heterogeneity of NEPC. Downstream analysis of single cell data was first completed on individual samples to identify distinct subpopulations of cells within each tumor. Then, integration analysis was performed to identify common and unique neuroendocrine populations across the different tumors. We profiled the transcriptome of 19,361 cells captured from the eight NEPCs. On an individual sample analysis, we detected 3 to 8 different subpopulations in each tumor, where every subpopulation displayed distinct biological properties such as epithelial mesenchymal transition, quiescence and stemness. Data integration of all samples revealed 16 subpopulations of tumor cells across all patients, of which 10 populations were primarily unique to one patient. Enriched pathway analyses revealed heterogeneous expression of most cancer hallmarks and oncogenic pathways across subpopulations, although some pathways were common to several neuroendocrine subpopulations such as EMT, P53 and KRAS. The detection of heterogeneous subpopulations in NEPC provides novel insight into why finding effective treatments for these aggressive tumors is challenging. Future work should focus on further evaluation of common druggable pathways that are shared across NEPC subpopulations. Alternatively, efforts could look at combination therapies that could effectively target these heterogeneous tumors. Citation Format: Rosalia Quezada Urban, Shivakumar Keerthikumar, Ashlee K. Clark, Laura H. Porter, Mitchell G. Lawrence, Renea A. Taylor, Gail P. Risbridger, Roxanne Toivanen, David L. Goode. Single cell RNA analysis reveals heterogeneous sub populations in aggressive variants of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4076.
Safety and Tolerability of MEDI0562, an OX40 Agonist mAb, in Combination with Durvalumab or Tremelimumab in Adult Patients with Advanced Solid Tumors
Authors: Jonathan W. Goldman, Sarina A. Piha-Paul, Brendan Curti, Katrina S. Pedersen, Todd M. Bauer, Stefanie L. Groenland, Richard D. Carvajal, Vaishali Chhaya, Gray Kirby, Kelly McGlinchey, Scott A. Hammond, Katie Streicher, Danielle M. Townsley, Young Kwang Chae, Jens Voortman, Aurelien Marabelle, John Powderly
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Combination therapies targeting immunologic checkpoints have shown promise in treating multiple tumor types. We report safety and tolerability of MEDI0562, a humanized IgG1K OX40 mAb, in combination with durvalumab (anti-PD-L1), or tremelimumab (anti-CTLA-4), in adult patients with previously treated advanced solid tumors. Patients and Methods: In this phase I, multicenter, open-label study, patients received escalating doses of MEDI0562 (2.25, 7.5, or 22.5 mg) every 2 weeks in combination with durvalumab (1,500 mg) or tremelimumab (75 or 225 mg) every 4 weeks, intravenously, until unacceptable toxicity or progressive disease. Tumor assessments were performed every 8 weeks. The primary objective was to evaluate safety and tolerability. Results: Among the 27 and 31 patients who received MEDI0562 + durvalumab or MEDI0562 + tremelimumab, 74.1% and 67.7% reported a treatment-related adverse event (AE), and 22.2% and 19.4% experienced a treatment-emergent AE that led to discontinuation, respectively. The MTD of MEDI0562 + durvalumab was 7.5 mg MEDI0562 + 1,500 mg durvalumab; the maximum administered dose of MEDI0562 + tremelimumab was 22.5 mg MEDI0562 + 225 mg tremelimumab. Three patients in the MEDI0562 + durvalumab arm had a partial response. The mean percentage of Ki67+CD4+ and Ki67+CD8+ memory T cells increased by &amp;gt;100% following the first dose of MEDI0562 + durvalumab or tremelimumab in all dose cohorts. A decrease in OX40+FOXP3 regulatory T cells was observed in a subset of patients with available paired biopsies. Conclusions: Following dose escalation, moderate toxicity was observed in both treatment arms, with no clear efficacy signals demonstrated.
Abstract 2925: Expanding the library of small molecule imaging probes for heparanase
Authors: Kelton Schleyer, Jun Liu, Zhishen Wang, Hua Guo, Lina Cui
Journal: Cancer Research (2022)

Abstract Heparanase is an enzyme highly involved in the progression of many types of cancer through its enzymatic processing of heparan sulfate proteoglycans. Unfortunately, research and clinical investigation of this target is hampered by the lack of simple, effective tools to detect its enzymatic activity. Despite the natural preference of heparanase to cleave polysaccharide substrates, we previously developed the first disaccharide-based fluorogenic probe for heparanase enzymatic activity, overcoming this deficiency in existing tools. However, the chemistry of the probe synthesis required installation of electron-withdrawing fluorine atoms on the fluorophore to facilitate activation by heparanase, a design strategy that excludes the use of many common imaging reporters. To accommodate a wider variety of imaging modalities for heparanase detection, we experimented with the addition of a collapsible linker with suitable electronegativity that can be easily tuned. Our results show that a tetra-fluorinated benzyl alcohol linker enables heparanase activation of a probe bearing any reporter, giving comparable results to our original fluorinated coumarin probe. This disaccharide-linker scaffold holds potential for accessing a broader scope of heparanase imaging probes for laboratory and clinical applications of this burgeoning biomarker. Citation Format: Kelton Schleyer, Jun Liu, Zhishen Wang, Hua Guo, Lina Cui. Expanding the library of small molecule imaging probes for heparanase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2925.
Abstract 5548: PB101 simultaneously targets tumor angiogenesis and immunity and enhances the efficacy of PD-L1 immune checkpoint blockade
Authors: Hannah Yang, Seung Joon Lee, Hyun-Gul Yang, Won Suk Lee, Jaekyung Cheon, Beodeul Kang, Sung-Eun Kim, Hyeseong Lim, Hong Jae Chon, Chan Kim
Journal: Cancer Research (2022)

Abstract Introduction: Tumor vasculature plays an important role in promoting tumor progression and immune evasion. Previously, we developed PB101, a novel glycosylated decoy receptor that can neutralize VEGF-A, VEGF-B, and PlGF, and demonstrated that it potently inhibits tumor angiogenesis, thereby retarding tumor growth and metastasis. However, its impact on tumor microenvironment (TME), especially anti-cancer immunity, has not been fully elucidated. Here, we investigated distinct modes of immune modulation by PB101 compared with other anti-angiogenic agents, and evaluated its immunotherapeutic potential when combined with immune checkpoint inhibitors (ICIs). Methods: MC38 colon or Hepa-V liver cancer-bearing mice were treated with PB101 or other anti-angiogenic agents with or without various ICIs. The TME was evaluated by histologic, flow cytometric, and Nanostring immune profiling analyses. Results: PB101 markedly suppressed MC38 colon and Hepa-V liver cancer growth in vivo. It simultaneously inhibited both VEGF and PlGF signaling within the TME, thus suppressing tumor angiogenesis. PB101 also induced extensive immune remodeling of the TME. PB101 enhanced intratumoral dendritic cells, but reduced M2-like tumor-associated macrophages. Moreover, PB101 resulted in high influx of activated CD8+, but not CD4+, T cells into the TME. PB101 exhibited the most prominent immune-modulating effect compared with other vascular targeting agents. When combined with various ICIs, PB101 had the greatest synergism with anti-PD-L1 antibody, inducing complete tumor regression and long-term survival. Furthermore, PB101-based combination immunotherapy induced a durable and protective immunity against subcutaneous tumor re-challenge and hematogenous lung metastasis. Conclusion: PB101 elicited strong anti-tumor immunity more effectively than other anti-angiogenic agents. PB101 can strengthen the immunotherapeutic efficacy of PD-L1 inhibitor by establishing a potent and durable immune memory. The combination of PB101 and PD-LI needs to be further validated in clinical trials. Citation Format: Hannah Yang, Seung Joon Lee, Hyun-Gul Yang, Won Suk Lee, Jaekyung Cheon, Beodeul Kang, Sung-Eun Kim, Hyeseong Lim, Hong Jae Chon, Chan Kim. PB101 simultaneously targets tumor angiogenesis and immunity and enhances the efficacy of PD-L1 immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5548.
Abstract 5024: Aging patterns in five disparate cancer entities indicate a novel senescent cell population with therapeutic targetability
Authors: Dominik Saul, Robyn Laura Kosinsky
Journal: Cancer Research (2022)

Abstract Human aging is associated with molecular changes and cellular degeneration, resulting in a significant increase in cancer incidence with age. Whether aging as its own entity can be initiator of putative cancerous developments, the transcriptional changes underlying the cancerous development itself are largely unknown. Here, we analyzed publicly available bulk RNA sequencing data of 328 control vs. 453 cancer samples in combination with single cell sequencing datasets from 49 control vs. 105 cancer patients. Using widely accepted aging-associated gene sets, we assembled key features of aging and their reflection in cancer development in five distinct cancer entities with an age-dependent increase of incidence, i.e. chronic myeloid leukemia (CML), colorectal cancer (CRC), hepatocellular carcinoma (HCC), lung cancer (LC) and pancreatic ductal adenocarcinoma (PDAC). After confirmation of the aging/senescence-induced gene (ASIG) expression to be upregulated in malignant diseases compared to healthy controls, we elucidated the importance of ASIGs during single cell development, making use of pseudotime analyses. In each entity, distinct temporally late enrichment states were carved out, and their transcriptional connectivity next to epigenetic control verified. Remarkably, we were able to demonstrate that all cancer entities analyzed in this study comprised cell populations expressing ASIGs. Except for pancreatic cancer, all entities accounted for subpopulations with aging associated patterns. Using a novel pipeline to repurpose FDA-approved drugs and combinations on a single cell level, we discovered a path for novel treatment regimen on a tumor-specific basis. These respective cellular subpopulations demonstrate pillars of susceptibility within the complex tumor microenvironment and serve as a basis for future studies on the role of aging and senescence in human malignancies. Citation Format: Dominik Saul, Robyn Laura Kosinsky. Aging patterns in five disparate cancer entities indicate a novel senescent cell population with therapeutic targetability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5024.
Abstract 3326: Uncovering the molecular mechanisms which predict sensitivity to a novel src kinase inhibitor NXP900 to inform personalized healthcare strategies
Authors: Neil Carragher, Rebecca Hughes, Valerie Brunton, Asier Unciti-broceta, Iñigo Lanzagorta-Calvillo, Carolin Temps, Enrique Poradosu
Journal: Cancer Research (2022)

Abstract We have previously described the discovery of a highly potent, selective and orally bioavailable Src kinase inhibitor NXP900 with a unique binding mode relative to other Src inhibitors under clinical development or approved (Temps et al 2021). This unique binding mode locks SRC in its native inactive conformation, thereby inhibiting both enzymatic and scaffolding functions. Also, in contrast to other Src inhibitors in the clinic, NXP900 exhibits a unique target selectivity profile with 1000 fold selectivity for Src over Abl kinase. The aim of this current study was to perform broad cancer cell line panel screening to inform disease positioning and identify predictive biomarkers of sensitivity for this novel class of Src kinase inhibitor. We describe the results of extensive cancer cell line panel profiling across a suite of 2-dimensional(D) and 3-D in vitro cell viability and high content phenotypic profiling assays that has revealed clear patterns of cell line sensitivity and insensitivity. Among the most sensitive cell line subtypes are, squamous cell carcinoma, Arid1A mutant ovarian clear cell carcinoma and subtypes of breast luminal A and triple negative breast cancer cell lines. HER2+ breast cancer lines appear insensitive to NXP900 indicating HER2 as a potential driver of resistance to NXP900. Further in-depth bioinformatic analysis of genetic and transcriptomic profiles of sensitive cell lines has identified putative biomarkers to support patient selection and personalized healthcare strategies. These studies demonstrate the identification of cancer cell lines which exhibit high sensitivity to NXP900 and which can be grouped into discrete molecular subtypes based on gene mutation status, transcriptomics and histotype. Our result provide an indication of patient subgroups which may exhibit optimal therapeutic response to NXP900 and provide data to guide further preclinical, biomarker and clinical development. Temps C et al., Cancer Res. 2021 Nov 1;81(21):5438-5450. doi: 10.1158/0008-5472.CAN-21-0613. Citation Format: Neil Carragher, Rebecca Hughes, Valerie Brunton, Asier Unciti-broceta, Iñigo Lanzagorta-Calvillo, Carolin Temps, Enrique Poradosu. Uncovering the molecular mechanisms which predict sensitivity to a novel src kinase inhibitor NXP900 to inform personalized healthcare strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3326.
Abstract 3695: Overexpression of HSD17B13 induced G1 arrest in hepatic cell lines detected by anti-HSD17B13 recombinant rabbit monoclonal antibody
Authors: Tianli Qu, Lipeng Wu, Jina Yom, Zhaoying Guo, Xiaomin Hu, Qi Ren, Qian Niu, Ruei-Shiuan Lin, Dezhong Yin, Xuan Liu, Fu Wei
Journal: Cancer Research (2022)

Abstract Hepatocellular carcinoma (HCC) is one of the most prevalent tumors worldwide. Hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), which was newly identified as a liver lipid droplet associated protein, was recently found to be down-regulated in HCC. However, the effects of HSD17B13 on the underlying mechanisms of HCC have not yet been fully explored. For this purpose, HSD17B13 gene was knockdown with CRISPER/Cas9 technique in several HCC cell lines. HSD17B13 expression was detected by Flow cytometry and Western blotting with recombinant rabbit monoclonal antibodies (clone OTIR3G2 and OTIR5C10) against HSD17B13 which were screened for use in immunohistochemistry, western blot, and ELISA application. Overexpressed HSD17B13 induces hepatic cell line G1 capture and increases several G1 arrest-related protein expression, including p21, p27, MMP2 and MMP3. Then the proliferation and cell cycle were suppressed. HSD17B13 gene knockdown will reverse the suppression. These data indicated that HSD17B13 play important roles in the progression of HCC lesions. HSD17B13 might be a potential immune-oncology marker for HCC. Citation Format: Tianli Qu, Lipeng Wu, Jina Yom, Zhaoying Guo, Xiaomin Hu, Qi Ren, Qian Niu, Ruei-Shiuan Lin, Dezhong Yin, Xuan Liu, Fu Wei. Overexpression of HSD17B13 induced G1 arrest in hepatic cell lines detected by anti-HSD17B13 recombinant rabbit monoclonal antibody [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3695.